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Cited by 47Antiplatelet Therapy and Cardiovascular DiseasesAcute Ischemic Stroke ManagementAcute Myocardial Infarction Research

Effect of Addition of Clopidogrel to Aspirin on Mortality: Systematic Review of Randomized Trials

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Palacio, Santiago, Hart, Robert G., Pearce, Lesly A., Benavente, Oscar R.·2012·Stroke
DOI 10.1161/strokeaha.112.656173PMC PMC3970708
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Abstract

Background and Purpose—: In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta-analysis of published randomized trials. Methods—: Randomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow-up of ≥14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported. Results—: Twelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days–3 months; OR, 0.93; 95% CI, 0.87–0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91–1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97–1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74–0.91). Conclusions—: The addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction. Clinical Trial Registration—: URL: http//www.clinicaltrials.gov . Unique identifier: NCT00059306.

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  • Many stroke trials have not explicitly separated ischaemic stroke subtypes, so they may have missed subtype-specific differences in treatment response.

    “Many trials have not differentiated ischaemic stroke subtypes explicitly, potentially overlooking any differences in treatment response between subtypes.18”

    From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [18]

  • Clopidogrel plus aspirin versus aspirin alone caused an excess of haemorrhage and death in patients with lacunar stroke, possibly because lacunar patients lacked large artery atheromatous disease to prevent, which is further evidence that SVD is largely non-atheromatous.

    “Clopidogrel plus aspirin versus aspirin alone caused an excess of haemorrhage (mostly systemic) and death in patients with lacunar stroke,13,76 possibly because patients with lacunar as opposed to other ischaemic stroke subtypes lacked any large artery atheromatous disease to prevent (eg myocardial infarction, large artery stroke, etc),18 further evidence of the largely non-atheromatous nature of”

    From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [18]

  • Patients without atheroma may receive less long-term benefit from anti-atheromatous treatments.

    “However it may be important to differentiate any due to focal atheroma from non-atheromatous lacunar ischaemic stroke as patients without atheroma may get less long term benefit from anti-atheromatous treatments.13,18,76”

    From Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging (2013) · cites this paper as [18]

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Authors
Palacio, S., Hart, R. G., Pearce, L. A., & Benavente, O. R.
Affiliations
University of British Columbia (CA)
ORCID
Venue
Stroke
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2012-08
Volume
43
Issue
8
Pages
2157-2162
ISSN
  • 0039-2499 (ISSN-L)
  • 1524-4628
DOI
10.1161/strokeaha.112.656173
PMC
PMC3970708
OpenAlex
W2099852184
Cited by
47
References
35
Citations by year
2026: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 9 · 2013: 5 · 2012: 5
FWCI
5.14
Type
journal article
Language
en
Open access
Locations
  • Stroke (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Neurological Disorders and Stroke (U01NS038529)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords
clopidogrel, aspirin, combination antiplatelet therapy, mortality, fatal hemorrhage, myocardial infarction, SPS3 trial, lacunar stroke, vascular disease, vascular risk factors
MeSH terms
Clopidogrel, Adult, Aged, Aspirin, Cause of Death, Cerebral Hemorrhage, Data Interpretation, Statistical, Double-Blind Method, Drug Therapy, Combination, Female, Hemorrhage, Humans, Male, Middle Aged, Myocardial Infarction, Platelet Aggregation Inhibitors, Ticlopidine, Randomized Controlled Trials as Topic, Treatment Outcome

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